title: GLP-1-derived nonapeptide GLP-1(28-36)amide represses hepatic gluconeogenic gene expression and improves pyruvate tolerance in high-fat diet-fed mice.
abstract: Certain "degradation" products of GLP-1 were found to possess beneficial effects on metabolic homeostasis. Here, we investigated the function of the COOH-terminal fragment of GLP-1, the nonapeptide GLP-1(28-36)amide, in hepatic glucose metabolism. C57BL/6 mice fed a high-fat diet (HFD) for 13 wk were injected intraperitoneally with GLP-1(28-36)amide for 6 wk. A significant reduction in body weight gain in response to HFD feeding was observed in GLP-1(28-36)amide-treated mice. GLP-1(28-36)amide administration moderately improved glucose disposal during glucose tolerance test but more drastically attenuated glucose production during pyruvate tolerance test, which was associated with reduced hepatic expression of the gluconeogenic genes Pck1, G6pc, and Ppargc1a. Mice treated with GLP-1(28-36)amide exhibited increased phosphorylation of PKA targets, including cAMP response element-binding protein (CREB), ATF-1, and β-catenin. In primary hepatocytes, GLP-1(28-36)amide reduced glucose production and expression of Pck1, G6pc, and Ppargc1a, which was associated with increased cAMP content and PKA target phosphorylation. These effects were attenuated by PKA inhibition. We suggest that GLP-1(28-36)amide represses hepatic gluconeogenesis involving the activation of components of the cAMP/PKA signaling pathway. This study further confirmed that GLP-1(28-36)amide possesses therapeutic potential for diabetes and other metabolic disorders.
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada;
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ip
authors.forename: Weijuan
authors.initials: W
authors.lastname: Shao
authors.forename: Yu-Ting Alex
authors.initials: YT
authors.lastname: Chiang
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D005951:Glucose Tolerance Test; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; C560057:glucagon-like peptide-1(28-36)amide; D019289:Pyruvic Acid; D052216:Glucagon-Like Peptide 1
keywords: adenosine 3′,5′-cyclic monophosphate; glucagon-like peptide-1; hepatic glucose production; protein kinase A; type 2 diabetes